Neuronal cell death has been associated with various clinical conditions and diseases. These conditions and diseases include, for example, neurodegenerative diseases such as Alzheimer's disease, AIDS-related dementia, Huntington's disease, and Parkinson's disease. Neuronal cell death has been also associated with developmental retardation and learning impairments. These diseases and conditions are severely debilitating and have a lifelong impact on individuals diagnosed with such diseases and conditions.
It has previously been reported that Activity Dependent Neurotrophic Factor (ADNF) polypeptides can be used to prevent or reduce neuronal cell death. Activity Dependent Neurotrophic Factor I (ADNF I) polypeptide is secreted by astroglial cells in the presence of vasoactive intestinal peptide (VIP). The ADNF I polypeptide exhibits survival-promoting activity for neurons at surprisingly low, femtomolar concentrations (Brenneman & Gozes, J. Clin. Invest. 97:2299-2307 (1996)). Further studies identified peptide fragments of ADNF I that mimic the neurotrophic and neuroprotective properties of ADNF I. The shortest peptide (i.e., the active core site) that captured the survival-promoting activity of ADNF I was the peptide SALLRSIPA, designated as ADNF-9 or SAL (Brenneman et al., J. Pharm. Exp. Therp. 285:619-627 (1998)). Studies of related molecules to the ADNF I polypeptide resulted in the discovery of Activity Dependent Neuroprotective Protein (called ADNP or ADNF III interchangeably). This protein was cloned (Bassan et al., J. Neurochem. 72:1283-1293 (1999)) and was found to have an active peptide similar in biological activity to SAL. This peptide (i.e., the active core site) was NAPVSIPQ, designated as NAP.
ADNF polypeptides have been shown to prevent neuronal cell death both in vitro and in vivo. For example, ADNF polypeptides have been shown to prevent neuronal cell death associated with tetrodotoxin (electrical blockade), the β-amyloid peptide (the Alzheimer's disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immune deficiency virus envelope protein. In addition, daily injections of ADNF polypeptides to newborn apolipoprotein E-deficient mice accelerated the acquisition of developmental reflexes and prevented short-term memory deficits. See, e.g., Bassan et al., J. Neurochem. 72:1283-1293 (1999). Moreover, pretreatment with ADNF polypeptides has been previously shown to reduce numerous or various conditions associated with fetal alcohol syndrome in a subject. See, U.S.S.N. 09/265,511, filed Mar. 12, 1999. now U.S. Pat. No. 6,933,277.
Although ADNF polypeptides have unlimited potential as neuroprotectants and/or therapeutic agents, it would be advantageous to provide additional ADNF polypeptides that have different properties from the known ADNF polypeptides. For example, availability of a number of ADNF polypeptides with different affinities for their receptors would allow targeting specific receptors in different cell types. Furthermore, additional ADNF polypeptides would aid in designing a drug treatment regime that can be individually tailored for each patient affected by neurodegenerative disorders. Finally, knowledge regarding the mechanism of action of ADNF would be useful for aiding in drug treatment for patients affected by neurodegenerative disorders.